Arylsulfonyl-N,N-dialkyl-dithiocarbamates as Tumor Cell Growth Inhibitors: Novel Agents Targeting β-Tubulin?

Abstract

Reaction of sodium N,N-dimethyldithiocarbamate or N,N-diethyldithiocarbamate with arylsulfonyl halides afforded a series of arylsulfonyl-N,N-dialkyl-dithiocarbamates. The reactivity of these new derivatives with cysteine and glutathione has been investigated in order to identify derivatives that might label a cysteine residue of the heterodimeric protein tubulin which plays a critical physiological function in cell division and also possesses enzymatic activity as a GTP-ase. Since many antitumor drugs exert their action by binding to tubulin, inhibiting in this way microtubule association and provoking cell death, some of the most reactive compounds against the thiol reagents found in this work have been assayed for their antitumor activity. Indeed strong tumor cell growth inhibitory properties against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer has been found in vitro for some of the 4-halogeno-, 4-methyl- or 4-carboxyphenyl-substituted arylsulfo-nyl-N,N-dialkyl-dithiocarbamates. Furthermore, some of these derivative were shown to act as in vitro tubulin polymerization inhibitors using a turbidimetric assay.

Key Words:

• N,N-dialkyl-dithiocarbamates
• arylsulfonyl-N,N-dialkyl-dithiocarbamates
• tubulin
• antitumor agent